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J. Biol. Chem., Vol. 276, Issue 19, 15816-15822, May 11, 2001
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From the Cholesterol 7
Down-regulation of Cholesterol 7
-Hydroxylase
(CYP7A1) Gene Expression by Bile Acids in Primary Rat
Hepatocytes Is Mediated by the c-Jun N-terminal Kinase Pathway*
,,
Department of Medicine-Gastroenterology,
§ Department of Radiation Oncology, and ¶ Department of
Microbiology and Immunology, Virginia Commonwealth University, Medical
College of Virginia Campus, Richmond, Virginia 23298
-hydroxylase (CYP7A1), the
rate-limiting enzyme in the neutral pathway of bile acid biosynthesis,
is feedback-inhibited at the transcriptional level by hydrophobic bile
acids. Recent studies show that bile acids are physiological ligands
for farnesoid X receptor (FXR). Activated FXR indirectly represses
CYP7A1 transcription through induction of small heterodimer
protein (SHP-1). In this study, we provide evidence that bile acids
rapidly down-regulate CYP7A1 transcription via activation
of the JNK/c-Jun pathway. Furthermore, we demonstrate that SHP-1 is
also a direct target of activated c-Jun. In primary rat hepatocyte
cultures, taurocholate (TCA) strongly activated JNK in a time- and
concentration-dependent manner. Tumor necrosis factor-,
a potent activator of JNK, also rapidly activated JNK and
down-regulated CYP7A1 mRNA levels. Overexpression of
dominant-negative JNK1 or a transactivating domain mutant of c-Jun
significantly blocked the ability of TCA to down-regulate CYP7A1 mRNA. In contrast, overexpression of wild-type
c-Jun (c-Junwt) enhanced the repression of
CYP7A1 by TCA. Moreover, overexpression of
c-Junwt resulted in increased SHP-1 promoter activity.
Mutation of a putative AP-1 (c-Jun) element suppressed c-Jun-mediated
activation of the SHP-1 promoter construct. These results indicate that
the bile acid-activated JNK pathway plays a pivotal role in regulating CYP7A1 levels in primary rat hepatocytes.
*
This work was supported by National Institutes of Health
Grants PO1-DK38030 (to P. B. H.) and RO1-DK52825 (to P. D.) and by Department of Defense Career Development Award BC98-0148 (to P. D.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of
Microbiology and Immunology, Medical College of Virginia Campus,
Virginia Commonwealth University, P. O. Box 980678, Richmond, VA
23298-0678. Tel.: 804-828-2331; Fax: 804-828-0676; E-mail:
hylemon@hsc.vcu.edu.
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